US2022257570A1PendingUtilityA1
Calpain inhibitors and uses thereof for treating neurological disorders
Est. expiryJul 31, 2039(~13 yrs left)· nominal 20-yr term from priority
A61K 31/415A61K 31/433A61K 31/166A61K 31/55A61K 31/343A61P 25/28A61K 31/53A61P 25/00A61P 25/16A61K 9/10A61K 31/554A61K 31/19A61K 9/2059A61K 9/2018A61K 31/451A61K 45/06A61K 9/2013A61K 31/135A61K 31/5415A61K 31/4545A61K 9/4858A61K 9/0019A61K 31/138A61K 9/2054
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Claims
Abstract
Methods of treating neurological diseases and disorders associated with protein aggregation using calpain inhibitors are provided. Said neurological diseases associated with protein aggregation include polyglutamine expansion diseases such as Huntington's disease, Machado-Joseph disease, and spinocerebellar ataxias.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating a neurological disease or disorder associated with protein aggregation, the method comprising administering to a subject in need thereof a compound of Formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is —C 1-6 alkyl or —(CH 2 ) n —C 6-10 aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of: -halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 alkoxy, and —C 1-6 haloalkoxy;
Z is —NR 2 R 3 or —OR 4 ;
R 2 is -hydrogen or —C 1-6 alkyl;
R 3 is -hydrogen, —C 1-6 alkyl, —C 3-10 cycloalkyl, or —OR 4 ;
R 4 is -hydrogen or —C 1-6 alkyl;
Q is -5-10-membered heteroaryl optionally substituted with one, two, or three substituents independently selected from the group consisting of: -halo; —C 1-6 alkyl; —C 1-6 haloalkyl; —C 1-6 alkoxy; —C 1-6 haloalkoxy; and —C 6-10 aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of: -halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 alkoxy, and —C 1-6 haloalkoxy; or
Q is —C 6-10 aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of: -halo; —C 1-6 alkyl; —C 1-6 haloalkyl; —C 1-6 alkoxy; —C 1-6 haloalkoxy; and -5-10-membered heteroaryl optionally substituted with one, two, or three substituents independently selected from the group consisting of: -halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 alkoxy, and —C 1-6 haloalkoxy; and
n is 1 or 2.
2 . The method of claim 1 , wherein the compound is a compound of Formula (1-a)
wherein:
X is S or NR 5 ;
Y is CH or N;
R 5 is -hydrogen or —C 1-6 alkyl;
each R 6 is independently selected from the group consisting of: -halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 alkoxy, and —C 1-6 haloalkoxy; and
m is 0, 1, 2, or 3.
3 . The method of claim 2 , wherein X is S.
4 . The method of claim 2 , wherein X is NR 5 .
5 . The method of claim 4 , wherein R 5 is hydrogen or —CH 3 .
6 . The method of any one of claims 2 to 5 , wherein Y is CH.
7 . The method of any one of claims 2 to 5 , wherein Y is N.
8 . The method of any one of claims 2 to 7 , wherein each R 6 is independently —F, —Cl, —CH 3 , —CF 3 , —OCH 3 , or —OCF 3 .
9 . The method of any one of claims 2 to 8 , wherein m is 0.
10 . The method of any one of claims 2 to 8 , wherein m is 1.
11 . The method of any one of claims 2 to 8 , wherein m is 2.
12 . The method of any one of claims 2 to 8 , wherein m is 3.
13 . The method of claim 1 , wherein the compound is a compound of Formula (1-b)
wherein:
each R 7 is independently selected from the group consisting of: -halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 alkoxy, and —C 1-6 haloalkoxy; and
t is 0, 1, 2, or 3.
14 . The method of claim 13 , wherein each R 7 is independently —F, —Cl, —CH 3 , —CF 3 , —OCH 3 , or —OCF 3 .
15 . The method of claim 13 or 14 , wherein t is 0.
16 . The method of claim 13 or 14 , wherein t is 1.
17 . The method of claim 13 or 14 , wherein t is 2.
18 . The method of claim 13 or 14 , wherein t is 3.
19 . The method of any one of claims 1 to 18 , wherein Z is —NR 2 R 3 .
20 . The method of any one of claims 1 to 19 , wherein R 2 is -hydrogen.
21 . The method of any one of claims 1 to 20 , wherein R 3 is -hydrogen, —CH 3 , or -cyclopropyl.
22 . The method of any one of claims 1 to 20 , wherein R 3 is —OH or —OCH 3 .
23 . The method of any of claims 1 to 18 , wherein Z is —OR 4 .
24 . The method of claim 23 , wherein R 4 is -hydrogen or —CH 3 .
25 . A method of treating a neurological disease or disorder associated with protein aggregation, the method comprising administering to a subject in need thereof a compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
26 . The method of any one of claims 1 to 25 , the method further comprising administering to the subject one or more second pharmaceutical agents.
27 . The method of claim 26 , wherein the second pharmaceutical agent is selected from tetrabenazinem, deutetrabenazine, citalopram, escitalipram, fluoxetine, sertraline, quetiapine, risperidone, haloperidol, chlorpromazine, valproate, carbamazepine, lamotrigine, levodopa, baclofen, and botulinum toxin.
28 . The method of any one of claims 1 to 27 , wherein the neurological disorder associated with protein aggregation is a polyglutamine disease or disorder.
29 . The method of claim 28 , wherein the polyglutamine disorder is Huntington's disease, Machado-Joseph disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2), spinocerebellar ataxia type 6 (SCA6), spinocerebellar ataxia type 7 (SCA7), or spinocerebellar ataxia type 17 (SCA17).
30 . The method of claim 28 , wherein the neurological disorder associated with protein aggregation is Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis.Join the waitlist — get patent alerts
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